Process for the production of sulfonic esters

ABSTRACT

Sulfonic acid ester derivatives represented by the general formula (4) or (5) are produced by reacting an amino alcohol derivative represented by the general formula (1) or (2) with an organic sulfonyl halide represented by the general formula (3), in a mixed solvent composed of an aprotic organic solvent and water in the presence of a non-water-prohibiting inorganic base. This procedure can be carried out in a simple, easy, safe and economical manner while reducing the load on the environment.                  
 
Wherein n represents an integer of 0 to 5, A represents a phenyl group, which may be substituted, R represents a methanesulfonyl, ethanesulfonyl, p-toluenesulfonyl or p-nitrobenzenesulfonyl group and X represents a chloride, bromine or iodine atom.

This application is a divisional of application Ser. No. 10/067,784,filed Feb. 8, 2002 now U.S. Pat. No. 6,794,519, which is a continuationof PCT Application No. PCT/JP00/08277, filed Nov. 24, 2000, which claimsthe benefit of Japanese Application No. JP 2000-172509, filed Jun. 8,2000.

TECHNICAL FIELD

The present invention relates to a method of producing sulfonic acidester derivatives, which are useful as intermediates for the synthesisof fine chemicals such as medicinal compounds and agrochemicals,represented by the general formula (4):

or the general formula (5):

wherein n represents an integer of 0 to 5, A represents a phenyl group,which may be substituted, B and B′ may be the same or different and eachrepresents a phenyl group, which may be substituted, a straight orbranched alkyl group containing 1 to 4 carbon atoms or a hydrogen atom,D represents a straight or branched alkyl group containing 1 to 8 carbonatoms, which may be substituted, or a hydrogen atom, E represents astraight or branched alkylene group containing 1 to 8 carbon atoms,which may be substituted, F represents a straight or branched alkylgroup containing 1 to 8 carbon atoms, which may be substituted, and Rrepresents a methanesulfonyl, ethanesulfonyl, p-toluenesulfonyl orp-nitrobenzenesulfonyl group.

BACKGROUND ART

Known in the art for producing sulfonic acid ester derivativesrepresented by the above general formula (4) or (5) are the methodcomprising reacting the corresponding amino alcohol derivative with anorganic sulfonyl halide in an organic solvent in the presence of anorganic base, for example a tertiary amine such as triethylamine or anaromatic amine such as pyridine, or in such an organic base; and themethod comprising reacting the corresponding amino alcohol derivativewith an organic sulfonyl halide in an anhydrous organic solvent in thepresence of a water-prohibiting base such as sodium hydride or sodiumamide.

Specifically, there are known the method comprising reacting1-benzyl-3-pyrrolidinol with methanesulfonyl chloride or toluenesulfonylchloride in the presence of an organic base such as triethylamine orpyridine (JP-A-07-116138; J. Med. Chem., 35 (1992) 22, 4205–4213) andthe method comprising reacting 1-benzyl-3-pyrrolidinol withtoluenesulfonyl chloride in an anhydrous solvent such as benzene ortetrahydrofuran in the presence of a water-prohibiting base such assodium hydride or sodium amide (JP-A-51-125286; Laid-open EuropeanPantent EP-0928787), among others.

However, these known production methods have the following problems,among others:

-   1) When an organic base such as a tertiary amine or an aromatic    amine is used, the organic base is expensive. For isolating the    sulfonic acid ester formed as an intermediate for the synthesis of    fine chemicals such as medicinal compounds or agrochemicals, which    are required to be of high quality, a high-level of purification for    removal of the organic base, such as crystallization, distillation    and/or column chromatography, is required (since the product    sulfonic acid ester derivative itself is a kind of organic base, it    is difficult to purify the same by such a simple technique as phase    separation). The organic base is obtained as waste in an amount at    least one equivalent relative to the product sulfonic acid ester    derivatives.-   2) When a water-prohibiting base, such as sodium hydride or sodium    amide, is used, such water-prohibiting base itself is expensive.    Such water-prohibiting base has a safe problem in handling in using    it on a commercial scale.-   3) In all the known methods, a high-level of purification, for    example removal of the organic base by rectification, and/or    dehydration, is required if the solvent is to be recovered and    recycled. Such a purification process is economically difficult in    many cases and the solvent is discharged as waste in increased    amounts.

Thus, when evaluated as methods capable of reducing the load on theenvironment in the production of intermediates for high-quality finechemicals such as medicinal compounds and agrochemicals on a commercialscale and in an economical manner, the prior art methods have problems.

In view of the state of the art as mentioned above, it is an object ofthe present invention to provide a method of economically producing thesulfonic acid ester derivatives represented by the general formula (4)or (5), which are intermediates for the synthesis of fine chemicals suchas medicinal compounds or agrochemicals, which are required to be ofhigh quality, in a simple and easy and safe manner while reducing theload on the environment.

DISCLOSURE OF INVENTION

The present invention thus provides a method of producing a sulfonicacid ester derivative represented by the general formula (4):

or the general formula (5):

wherein n represents an integer of 0 to 5, A represents a phenyl group,which may be substituted, B and B′ are the same or different and eachrepresents a phenyl group, which may be substituted, a straight orbranched alkyl group containing 1 to 4 carbon atoms or a hydrogen atom,D represents a straight or branched alkyl group containing 1 to 8 carbonatoms, which may be substituted, or a hydrogen atom, E represents astraight or branched alkylene group containing 1 to 8 carbon atoms,which may be substituted, F represents a straight or branched alkylgroup containing 1 to 8 carbon atoms, which may be substituted and Rrepresents a methanesulfonyl, ethanesulfonyl, p-toluenesulfonyl orp-nitrobenzenesulfonyl group,

which comprises reacting an amino alcohol derivative represented by thegeneral formula (1):

or the general formula (2):

wherein n, A, B, B′, D, E and F are as defined above, with an organicsulfonyl halide represented by the general formula (3):R—X

wherein R is as defined above and X represents a chlorine, bromine oriodine atom,

in a mixed solvent composed of an aprotic organic solvent and water inthe presence of a non-water-prohibiting inorganic base.

In the following, the present invention is described in detail.

The amino alcohol derivative represented by the general formula (1):

or the general formula (2):

and to be used in the production method of the present invention can beproduced, for example, by the method described in JP-A-61-63652 or inJP-A-01-141600.

Referring to the above general formula (1), n represents an integer of 0to 5 and preferably is an integer of 0 to 4, more preferably an integerof 2 or 3.

The substituent A in the above general formula (1) or (2) is a phenylgroup, which may be substituted, and specifically includes anunsubstituted phenyl group, a nitro-substituted phenyl group, ahalo-substituted phenyl group, a phenyl group substituted by one or twolower alkoxyl groups or one or two lower alkyl groups, and the like.

The substituents B and B′ in the above general formula (1) or (2) may bethe same or different and each represents a phenyl group, which may besubstituted, a straight or branched alkyl group containing 1 to 4 carbonatoms, or a hydrogen atom. Specifically, there may be mentionedhydrogen; lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl and tert-butyl; unsubstituted phenyl,nitro-substituted phenyl, phenyl substituted by one or two lower alkoxylgroups, and the like.

The substituent D in the above general formula (1) represents a straightor branched alkyl group containing 1 to 8 carbon atoms, which may besubstituted, or a hydrogen atom. This alkyl group may be unsubstitutedor substituted by a substituent inert to the sulfonylation reaction, forexample a protected amino group such as a tertiary amino or acylaminogroup; a substituted carbonyl group such as a hydoxycarbonyl,alkoxycarbonyl, aminocarbonyl or acyl group; a protected hydroxyl groupsuch as an alkyloxy or acyloxy group; an aromatic group such as a phenylor pyridyl group; or the like.

The substituent E in the above general formula (1) represents a straightor branched alkylene group containing 1 to 8 carbon atoms, which may besubstituted, and the substituent F represents a straight or branchedalkyl group containing 1 to 8 carbon atoms, which may be substituted.The alkylene group and alkyl group may be unsubstituted or substitutedby such a substituent inert to the sulfonylation reaction as describedabove.

As specific examples of the amino alcohol derivative represented by theabove general formula (1) or (2), there may be mentionedN-benzyl-2-aziridinol, N-benzyl-3-azetidinol, N-benzyl-3-pyrrolidinol,N-benzyl-3-piperidinol, N-benzyl-4-piperidinol,N-benzhydryl-2-aziridinol, N-benzhydryl-3-azetidinol,N-benzhydryl-3-pyrrolidinol, N-benzhydryl-3-piperidinol,N-benzhydryl-4-piperidinol, N-trityl-2-aziridinol,N-trityl-3-azetidinol, N-trityl-3-pyrrolidinol, N-trityl-3-piperidinol,N-trityl-4-piperidinol, N-benzyl-3-methyl-2-aziridinol,N-benzyl-2-methyl-3-azetidinol, N-benzyl-4-methyl-3-pyrrolidinol,N-benzyl-4-methyl-3-piperidinol, N-benzyl-3-methyl-4-piperidinol,N-benzhydryl-3-methyl-2-aziridinol, N-benzhydryl-2-methyl-3-azetidinol,N-benzhydryl-4-methyl-3-pyrrolidinol,N-benzhydryl-4-methyl-3-piperidinol,N-benzhydryl-3-methyl-4-piperidinol, N-trityl-3-methyl-2-aziridinol,N-trityl-2-methyl-3-azetidinol, N-trityl-4-methyl-3-pyrrolidinol,N-trityl-4-methyl-3-piperidinol, N-trityl-3-methyl-4-piperidinol,N-benzyl-N-methyl-2-aminoethanol, N-benzyl-N-ethyl-2-aminoethanol,N-benzyl-N-methyl-3-aminopropanol, N-benzyl-N-ethyl-3-aminopropanol andthe like. Among these, N-benzyl-3-pyrrolidinol (i.e.1-benzyl-3-pyrrolidinol) is particularly preferred.

As specific examples of the sulfonic acid ester derivative representedby the above general formula (4) or (5) which can be produced accordingto the present invention, there may be mentioned N-benzyl-2-aziridinolmethanesulfonate, N-benzyl-3-azetidinol methanesulfonate,N-benzyl-3-pyrrolidinol methanesulfonate, N-benzyl-3-piperidinolmethanesulfonate, N-benzyl-4-piperidinol methanesulfonate,N-benzhydryl-2-aziridinol methanesulfonate, N-benzhydryl-3-azetidinolmethanesulfonate, N-benzhydryl-3-pyrrolidinol methanesulfonate,N-benzhydryl-3-piperidinol methanesulfonate, N-benzhydryl-4-piperidinolmethanesulfonate, N-trityl-2-aziridinol methanesulfonate,N-trityl-3-azetidinol methanesulfonate, N-trityl-3-pyrrolidinolmethanesulfonate, N-trityl-3-piperidinol methanesulfonate,N-trityl-4-piperidinol methanesulfonate, N-benzyl-3-methyl-2-aziridinolmethanesulfonate, N-benzyl-2-methyl-3-azetidinol methanesulfonate,N-benzyl-4-methyl-3-pyrrolidinol methanesulfonate,N-benzyl-4-methyl-3-piperidinol methanesulfonate,N-benzyl-3-methyl-4-piperidinol methanesulfonate,N-benzhydryl-3-methyl-2-aziridinol methanesulfonate,N-benzhydryl-2-methyl-3-azetidinol methanesulfonate,N-benzhydryl-4-methyl-3-pyrrolidinol methanesulfonate,N-benzhydryl-4-methyl-3-piperidinol methanesulfonate,N-bezhydryl-3-methyl-4-piperidinol methanesulfonate,N-trityl-3-methyl-2-aziridinol methanesulfonate,N-trityl-2-methyl-3-azetidinol methanesulfonate,N-trityl-4-methyl-3-pyrrolidinol methanesulfonate,N-trityl-4-methyl-3-piperidinol methanesulfonate,N-trityl-3-methyl-4-piperidinol methanesulfonate,N-benzyl-N-methyl-2-aminoethanol methanesulfonate,N-benzyl-N-ethyl-2-aminoethanol methanesulfonate,N-benzyl-N-methyl-3-aminopropanol methanesulfonate,N-benzyl-N-ethyl-3-aminopropanol methanesulfonate, N-benzyl-2-aziridinolp-toluenesulfonate, N-benzyl-3-azetidinol p-toluenesulfonate,N-benzyl-3-pyrrolidinol p-toluenesulfonate, N-benzyl-3-piperidinolp-toluenesulfonate, N-benzyl-4-piperidinol p-toluenesulfonate,N-benzhydryl-2-aziridinol p-toluenesulfonate, N-benzhydryl-3-azetidinolp-toluenesulfonate, N-benzhydryl-3-pyrrolidinol p-toluenesulfonate,N-benzhydryl-3-piperidinol p-toluenesulfonate,N-benzhydryl-4-piperidinol p-toluenesulfonate, N-trityl-2-aziridinolp-toluenesulfonate, N-trityl-3-azetidinol p-toluenesulfonate,N-trityl-3-pyrrolidinol p-toluenesulfonate, N-trityl-3-piperidinolp-toluenesulfonate, N-trityl-4-piperidinol p-toluenesulfonate,N-benzyl-3-methyl-2-aziridinol p-toluenesulfonate,N-benzyl-2-methyl-3-azetidinol p-toluenesulfonate,N-benzyl-4-methyl-3-pyrrolidinol p-toluenesulfonate,N-benzyl-4-methyl-3-piperidinol p-toluenesulfonate,N-benzyl-3-methyl-4-piperidinol p-toluenesulfonate,N-benzhydryl-3-methyl-2-aziridinol p-toluenesulfonate,N-benzhydryl-2-methyl-3-azetidinol p-toluenesulfonate,N-benzhydryl-4-methyl-3-pyrrolidinol p-toluenesulfonate,N-benzhydryl-4-methyl-3-piperidinol p-toluenesulfonate,N-benzhydryl-3-methyl-4-piperidinol p-toluenesulfonate,N-trityl-3-methyl-2-aziridinol p-toluenesulfonate,N-trityl-2-methyl-3-azetidinol p-toluenesulfonate,N-trityl-4-methyl-3-pyrrolidinol p-toluenesulfonate,N-trityl-4-methyl-3-piperidinol p-toluenesulfonate,N-trityl-3-methyl-4-piperidinol p-toluenesulfonate,N-benzyl-N-methyl-2-aminoethanol p-toluenesulfonate,N-benzyl-N-ethyl-2-aminoethanol p-toluenesulfonate,N-benzyl-N-methyl-3-aminopropanol p-toluenesulfonate,N-benzyl-N-ethyl-3-aminopropanol p-toluenesulfonate and the like.

The organic sulfonyl halide represented by the general formula (3):R—X

wherein R represents a methanesulfonyl, ethanesulfonyl,p-toluenesulfonyl or p-nitrobenzenesulfonyl group and X represents achlorine, bromine or iodine atom, preferably a chlorine atom, which isto be used in the production method of the present invention, comprisesat least one species selected from the group consisting ofmethanesulfonyl chloride, ethanesulfonyl chloride, p-toluenesulfonylchloride, p-nitrobenzenesulfonyl chloride, methanesulfonyl bromide,ethanesulfonyl bromide, p-toluenesulfonyl bromide,p-nitrobenzenesulfonyl bromide, methanesulfonyl iodide, ethanesulfonyliodide, p-toluenesulfonyl iodide and p-nitrobenzenesulfonyl iodide.Among these, methanesulfonyl chloride is particularly preferred from theviewpoint of ready availability and reactivity.

The amount of the above organic sulfonyl halide can be selected takinginto consideration the amino alcohol derivative species represented bythe above general formula (1) or (2), the solvent composition to be usedin carrying out the reaction, and the reaction efficiency, among others.Generally, it is used in an amount of about 1 to 10 moles relative tothe amino alcohol derivative represented by the above general formula(1) or (2).

The non-water-prohibiting inorganic base to be used in the productionmethod of the present invention is not a water-prohibiting base such assodium hydride or sodium amide but is an inorganic base commonly andreadily used as a base incapable of reacting with water but capable ofoccurring in the form of an aqueous solution. There may specifically bementioned alkali metal hydroxides, carbonates and hydrogen carbonates,for example lithium hydroxide, sodium hydroxide, potassium hydroxide;lithium carbonate, sodium carbonate, potassium carbonate; lithiumhydrogen carbonate, sodium hydrogen carbonate, potassium hydrogencarbonate, etc. Among these, sodium hydroxide and potassium hydroxideare preferred. These may be used singly or two or more of them may beused in combination. These inorganic bases may be added to the reactionsystem as they are, or mixtures prepared in advance from such inorganicbases and a reaction solvent may be used.

The above-mentioned inorganic base may be used in an amount at least toneutralize the hydrohalic acid formed in an equimolar amount asbyproduct upon the reaction between the amino alcohol of general formula(1) or (2) with the organic sulfonyl halide of general formula (3) toform the sulfonic acid ester derivative of general formula (4) or (5) aswell as the sulfonic acid and hydrohalic acid formed as byproducts uponhydrolysis of the organic sulfonyl halide of general formula (3) in thereaction mixture and to maintain the alkalinity of the reaction mixture,although it is not particularly restricted. Generally, the base is usedin an amount of about 1 to 5 moles relative to the organic sulfonylhalide of general formula (3).

The reaction solvent to be used in the production method of the presentinvention is a mixed solvent composed of an aprotic organic solvent andwater. The aprotic organic solvent includes, among others, hydrocarbonssuch as benzene, toluene and cyclohexane; ethers such as diethyl ether,tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylenechloride; and like organic solvents. These may be used singly or two ormore of them may be used in admixture. Among them, the use of an organicsolvent capable of forming a two-phase system with the aqueous phasecontaining the inorganic base, for example benzene, toluene,cyclohexane, diethyl ether or methylene chloride, is preferred, and theuse of toluene is particularly preferred.

The amount of the aprotic organic solvent, though not particularlyrestricted, may be not less than one tenth, by weight, of the aminoalcohol derivative of general formula (1) or (2). Generally, the aboveamount is 1 to 10 times, preferably 2 to 5 times, by weight, the amountof the amino alcohol derivative of general formula (1) or (2).

The amount of water in the above-mentioned reaction solvent ispreferably 0.5 to 50 times, more preferably 1 to 10 times, still morepreferably 1 to 3 times, by weight, that of the above inorganic base.

In the production method of the present invention, it is preferred thatthe aprotic organic solvent phase and the inorganic base-containingaqueous phase form a two-phase system. By forming such system, a higherreaction yield can be obtained and the purification of the product byphase separation becomes easier as compared with the case where theaprotic organic solvent and the inorganic base-containing water form aone-phase system.

The above reaction may be carried out at a temperature within the rangeof from the solidifying point to the boiling point of the reactionmixture, preferably −25° C. to 60° C., more preferably −20 to 30° C.,still more preferably −10 to 15° C.

Preferably, the above reaction is carried out in an inert atmosphere,such as a nitrogen atmosphere, so that side reactions such as oxidationmay be suppressed as far as possible.

The above reaction is carried out in mixing the amino alcohol derivativeof general formula (1) or (2) with the organic sulfonic halide ofgeneral formula (3) in a reaction solvent composed of an aprotic organicsolvent and water in the presence of a non-water-prohibiting inorganicbase. Since this reaction is an exothermic one, it is generally carriedout in a reactor in which the reaction mixture can be maintained undergood mixing conditions and in which the reaction can be carried outwhile removing the heat of reaction. When the reaction is carried outbatchwise in an ordinary tank reactor equipped with a stirrer, forinstance, the reaction is preferably carried out either by the methodcomprising charging the inorganic base and the amino alcohol derivativeof general formula (1) or (2) into a reaction solvent composed of anaprotic organic solvent and water, starting stirring/mixing and thengradually adding the organic sulfonyl halide of general formula (3) orby the method comprising charging the amino alcohol derivative ofgeneral formula (1) or (2) into a reaction solvent composed of anaprotic organic solvent and water, starting stirring/mixing and thengradually adding the organic sulfonyl halide of general formula (3) andthe inorganic base. This reaction can also be carried out by the flowmethod using, for example, a tubular reactor, a multistage tank-typeflow reactor, a rotary or falling thin-film reactor or the like. In thiscase, the reaction is preferably carried out by introducing a mixture ofthe amino alcohol derivative of general formula (1) or (2) and thereaction solvent, a mixture of the inorganic base and the reactionsolvent and a mixture of the organic sulfonyl halide of general formula(3) and the reaction solvent concurrently into the reactor for mixingthereof within the reactor.

In any of the above-mentioned methods of carrying out the reaction, itis also possible to carry out the reaction in a multistage manner bycharging a portion each of the intended amounts of the inorganic baseand sulfonyl halide relative to a predetermined amounts of the aminoalcohol derivative of general formula (1) or (2) and, after completionof the reaction of that part, discharging the aqueous phase and furtheradding water, the inorganic base and sulfonyl halide, and repeating thisprocedure according to need. By carrying out the reaction in such amultistage manner, it is possible to carry out the intended reaction ina reactor smaller in size as compared with the case where the reactionis carried out in a one-stage manner.

In cases where the amino alcohol derivative of general formula (1) or(2) is in an optically active form, any change in optical purity due tosteric inversion, racemization or the like is not observed aftercarrying out the reaction according to the present invention and, thus,the sulfonyl ester derivative of general formula (4) or (5) can beobtained in an optically active form having the configurationcorresponding to that of the amino alcohol derivative of general formula(1) or (2).

The final reaction mixture containing the sulfonic acid ester derivativeof general formula (4) or (5) synthesized by the method of the presentinvention can be readily deprived of the hydrohalic acid and organicsulfonic acid formed during the reaction, the salt formed from the basecharged for reaction and the excess base by a mere phase separationprocedure, it is possible to very easily obtain a solution of thesulfonic acid ester derivative in the aprotic organic solvent.

This phase separation procedure for obtaining such a solution of thesulfonic acid ester derivative in the aprotic organic solvent may becombined with such a treatment procedure(s) as pH adjustment, solventextraction or/and washing. If the precipitation of a salt, for examplethe salt of the hydrohalic acid or organic sulfonic acid with theinorganic base, is found in the final reaction mixture, it is alsopossible to dissolve the salt by adding water in an amount required fordissolving the salt to thereby facilitate the phase separationprocedure. Furthermore, it is possible to combine these procedures witha solvent removing procedure to thereby obtain the sulfonic acid esterderivative as a concentrate.

Thus, for example, when 1-benzyl-3-pyrrolidinol is reacted withmethanesulfonyl chloride in the presence of sodium hydroxide using amixed solvent composed of toluene and water as the reaction solvent andthe reaction mixture is obtained in the form of a two-phase systemcomposed of a toluene phase and an aqueous phase, it is possible toobtain 1-benzyl-3-pyrrolidinol methanesulfonate as a concentrate byremoving the solvent by concentrating, under reduced pressure, from thetoluene solution obtained by phase separation of the reaction mixture,after or without washing the toluene phase with water.

The sulfonic acid ester derivative represented by the general formula(4) or (5) as obtained according to the present invention can be appliedto the production of fine chemicals, such as medicinal compounds andagrochemicals, without any high-level purification, as mentionedhereinabove. It is also possible, however, to highly purify thederivative by further using such isolation/purification procedures asdistillation, crystallization and column chromatography, employed eithersingly or in combination.

In the step of recovering the sulfonic acid ester derivative as aconcentrate under reduced or ordinary pressure from the aprotic organicsolvent solution containing the sulfonic acid ester derivative asobtained after the above-mentioned phase separation procedure, combinedwith such a treatment method(s) as pH adjustment, solvent extractionor/and washing, the aprotic organic solvent recovered as a distillatefraction is free of any organic base, the aprotic organic solvent forthe reaction is used in the form of a mixed solvent with water accordingto the method of the present invention for producing sulfonic acidesters, hence can be reused as the reaction solvent in the productionmethod of the present invention without any high-level purificationprocedure such as rectification or dehydration,.

BEST MODES FOR CARRYING OUT THE INVENTION

The following examples illustrate the present invention in more detail.These examples are, however, by no means limitative of the scope of theinvention.

EXAMPLE 1

(S)-1-Benzyl-3-pyrrolidinol (44.35 g), 132.77 g of toluene and 166.71 gof a 30% aqueous solution of NaOH were respectively weighed and placedin a 500-mL four-necked flask. While the mixture was stirred, the flaskinside temperature was lowered to 6.5° C. Then, 63.14 g ofmethanesulfonyl chloride was added dropwise over 4 hours and 14 minutesat a flask inside temperature of 5 to 10° C. Water (35 mL) was added todissolve the NaCl which had precipitated out in the aqueous phase, andthe mixture was separated into the toluene phase and aqueous phase.

The toluene phase was concentrated using an evaporator, wherebyconcentrated (S)-1-benzyl-3-pyrrolidinol methanesulfonate was obtainedas a pale-yellow oil in a yield of 94.8 mole percent. In the step ofconcentration, the toluene was recovered with a recovery rate of 95%.

EXAMPLE 2

Except that the toluene recovered in Example 1 was used as the reactionsolvent without any purification procedure, the procedure of Example 1was otherwise repeated to give concentrated (S)-1-benzyl-3-pyrrolidinolmethanesulfonate as a pale-yellow oil in a yield of 94.0 mole percent.

EXAMPLE 3

N-Benzyl-N-methyl-ethanolamine (20.73 g), 61.94 g of toluene and 83.41 gof a 30% aqueous solution of NaOH were respectively weighed and placedin a 300-mL four-necked flask. While the mixture was stirred, the flaskinside temperature was lowered to 6.8° C. Then, 31.68 g ofmethanesulfonyl chloride was added dropwise over 3 hours and 17 minutesat a flask inside temperature of 5 to 10° C. Water (33 mL) was added todissolve the NaCl which had precipitated out in the aqueous phase, andthe mixture was separated into the toluene phase and aqueous phase. Atoluene solution of N-benzyl-N-methyl-ethanolamine methanesulfonate wasthus obtained in a yield of 68.8 mole percent.

EXAMPLE 4

(S)-1-Benzyl-3-pyrrolidinol (44.32 g), 132.88 g of toluene and 166.95 gof a 30% aqueous solution of NaOH were respectively weighed and placedin a 500-mL four-necked flask. While the mixture was stirred, the flaskinside temperature was lowered to 6.0° C. Then, 104.94 g oftoluenesulfonyl chloride was added in divided portions at an interval ofabout 5 g/10 minutes over 3 hours and 10 minutes at a flask insidetemperature of 5 to 10° C. Water (37 mL) was added to dissolve the NaClwhich had precipitated out in the aqueous phase, and the mixture wasseparated into the toluene phase and aqueous phase. A toluene solutionof (S)-1-benzyl-3-pyrrolidinol toluenesulfonate was thus obtained in ayield of 85.5 mole percent.

EXAMPLE 5

(S)-1-Benzyl-3-pyrrolidinol (22.17 g), 66.56 g of tetrahydrofuran and83.68 g of a 30% aqueous solution of NaOH were respectively weighed andplaced in a 300-mL four-necked flask. The mixture was stirred, whereuponthe tetrahydrofuran phase and aqueous phase formed a two-phase system.While the above mixture was stirred, the flask inside temperature waslowered to 6.8° C. Then, 31.65 g of methanesulfonyl chloride was addeddropwise over about 4 hours at a flask inside temperature of 5 to 10° C.Water (24 mL) was added to dissolve the NaCl which had precipitated outin the aqueous phase, and the mixture was separated into thetetrahydrofuran phase and aqueous phase.

The same amount of a 30% aqueous solution of NaOH as above was added tothe tetrahydrofuran phase thus obtained, and the same amount ofmethanesulfonyl chloride as above was added dropwise to allow thereaction to proceed, under the same condition as above. The same amountof water as above was added, and the mixture was separated into thetetrahydrofuran phase and aqueous phase.

After two further repetitions of this procedure, a tetrahydrofuransolution of (S)-1-benzyl-3-pyrrolidinol methanesulfonate was obtained ina yield of 89.4%.

EXAMPLE 6

1-Benzyl-4-piperidinol (23.98 g), 168.66 g of toluene and 83.56 g of a30% aqueous solution of NaOH were respectively weighed and placed in a500-mL four-necked flask. While the mixture was stirred, the flaskinside temperature was lowered to 6.7° C. Then, 31.73 g ofmethanesulfonyl chloride was added dropwise over 4 hours and 30 minutesat a flask inside temperature of 5 to 10° C. Water (33 mL) was added todissolve the NaCl which had precipitated out in the aqueous phase, andthe mixture was separated into the toluene phase and aqueous phase. Atoluene solution of 1-benzyl-4-piperidinol methanesulfonate was thusobtained in a yield of 40.3 mole percent.

INDUSTRIAL APPLICABILITY

The present invention, which has the constitution mentioned above, makesit possible to prepare sulfonic acid ester derivatives represented bythe above general formula (4) or (5) from the amino alcohol derivativesrepresented by the above general formula (1) or (2) in a simple, easy,safe and economical manner while reducing the load on the environment.

1. A method of producing a sulfonic acid ester derivative represented bythe general formula (5):

wherein A represents a phenyl group, which may be substituted, B and B′are the same or different and each represents a phenyl group, which maybe substituted, a straight or branched alkyl group containing 1 to 4carbon atoms or a hydrogen atom, E represents a straight or branchedalkylene group containing 1 to 8 carbon atoms, which may be substituted,F represents a straight or branched alkyl group containing 1 to 8 carbonatoms, which may be substituted and R represents a methanesulfonyl,ethanesulfonyl, p-toluenesulfonyl or p-nitrobenzenesulfonyl group, whichcomprises reacting an amino alcohol derivative represented by thegeneral formula (2):

wherein A, B, B′, E and F are as defined above, with an organic sulfonylhalide represented by the general formula (3):R—X wherein R is as defined above and X represents a chlorine, bromineor iodine atom, in a mixed solvent composed of an aprotic organicsolvent and water in the presence of a non-water-prohibiting inorganicbase.
 2. The production method according to claim 1, wherein the aproticorganic solvent phase and the aqueous phase containing thenon-water-prohibiting inorganic base form a two-phase system.
 3. Theproduction method according to claim 1, wherein the amino alcoholderivative represented by the general formula (2) is in an opticallyactive form and the sulfonic acid ester derivative represented by thegeneral formula (5) is in an optically active form.
 4. The productionmethod according to claim 1, wherein the aprotic organic solvent istoluene.
 5. The production method according to claim 1, wherein thenon-water-prohibiting inorganic base comprises at least one speciesselected from the group consisting of lithium hydroxide, sodiumhydroxide, potassium hydroxide, lithium carbonate, sodium carbonate,potassium carbonate, lithium hydrogen carbonate, sodium hydrogencarbonate and potassium hydrogen carbonate.
 6. The production methodaccording to claim 5, wherein the non-water-prohibiting inorganic basecomprises at least one species selected from among sodium hydroxide andpotassium hydroxide.
 7. The production method according to claim 1,wherein the organic sulfonyl halide represented by the general formula(3) is methanesulfonyl chloride.
 8. The production method according toclaim 2, wherein the amino alcohol derivative represented by the generalformula (2) is in an optically active form and the sulfonic acid esterderivative represented by the general formula (5) is in an opticallyactive form.
 9. The production method according to claim 9, wherein theaprotic organic solvent is toluene.
 10. The production method accordingto claim 2, wherein the aprotic organic solvent is toluene.
 11. Theproduction method according to claim 2, wherein thenon-water-prohibiting inorganic base comprises at least one speciesselected from the group consisting of lithium hydroxide, sodiumhydroxide, potassium hydroxide, lithium carbonate, sodium carbonate,potassium carbonate, lithium hydrogen carbonate, sodium hydrogencarbonate and potassium hydrogen carbonate.
 12. The production methodaccording to claim 3, wherein the non-water-prohibiting inorganic basecomprises at least one species selected from the group consisting oflithium hydroxide, sodium hydroxide, potassium hydroxide, lithiumcarbonate, sodium carbonate, potassium carbonate, lithium hydrogencarbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.13. The production method according to claim 4, wherein thenon-water-prohibiting inorganic base comprises at least one speciesselected from the group consisting of lithium hydroxide, sodiumhydroxide, potassium hydroxide, lithium carbonate, sodium carbonate,potassium carbonate, lithium hydrogen carbonate, sodium hydrogencarbonate and potassium hydrogen carbonate.
 14. The production methodaccording to claim 2, wherein the organic sulfonyl halide represented bythe general formula (3) is methanesulfonyl chloride.
 15. The productionmethod according to claim 3, wherein the organic sulfonyl haliderepresented by the general formula (3) is methanesulfonyl chloride. 16.The production method according to claim 4, wherein the organic sulfonythalide represented by the general formula (3) is methanesulfonylchloride.
 17. The production method according to claim 5, wherein theorganic sulfonyl halide represented by the general formula (3) ismethanesulfonyl chloride.
 18. The production method according to claim6, wherein the organic sulfonyl halide represented by the generalformula (3) is methanesulfonyl chloride.